In the current era of effective prophylactic or pre-emptive ganciclovir therapy, cytomegalovirus (CMV) infections continue to pose a significant hazard for patients after hematopoietic stem cell transplantation (HSCT). CMV seronegative recipients of stem cells from seropositive donors (D+/R-) are at the highest risk for transplant-related mortality among all serogroup pairs (vs. D+/R+, D-/R+, or D-/R-). This is surprising, since only 15% of these patients develop primary CMV infection after transplantation as detected by CMV antigenemia assays. A detailed chart review of transplant-related mortality within the D+/Rcohort revealed a markedly higher mortality from invasive bacterial and fungal infections when compared to D-/R- transplant recipients (p<.001). Using a recently developed PCR assay, we have shown that an additional 20% of D+/R- patients develop subclinical CMV infection that is not detected by standard pp65 antigenemia assays, and does not lead to CMV disease. These patients have not received pre-emptive ganciclovir, obviating the role of this compound in the excess infectious mortality. A preliminary prospective study suggests that patients with subclinical CMV infection have an increased incidence of invasive bacterial and fungal infections. Importantly, subclinical CMV infection antedates the development of these fatal bacterial and fungal infections, and may thus be a marker for more severe immunosuppression. We hypothesize that it is the immunomodulatory effect of primary CMV infection that accounts for the increased incidence of bacterial and fungal infections in this population. This proposal seeks to define these issues more clearly. Initially, we will retrospectively define the frequency and timing of subclinical CMV infection among over 700 HSCT recipients via the testing of banked serum samples for the presence of CMV DNA. These findings will then be correlated with clinical outcomes, which include fatal and non-fatal bacterial and fungal infections. We will then design a prospective double-blind trial of CMV prophylaxis aimed at the prevention of invasive bacterial and fungal infections after transplantation. Finally, the pathogenesis of the interaction between CMV infection and invasive pulmonary aspergillosis (IPA) will be evaluated; routine bronchoscopy will be performed on all patients, and the pulmonary CMV load will be correlated with the incidence of subsequent pulmonary complications such as IPA. Whether CMV impairs the activity of pulmonary macrophages or alters T-helper cytokine profiles in the lungs will also be determined. These results will improve our understanding of the interaction between CMV and other infections in HSCT recipients, which will ultimately enable us to formulate more rational treatment strategies. This award will support my first step towards obtaining my long-term career goal, which is to be a proficient clinical investigator for infections in the immunocompromised host.